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Journal Article

14-3-3 proteins: an important regulator of autophagy in diseases.

Haoyuan Jia1, Zhaofeng Liang1, Xu Zhang1, Juanjuan Wang1, Wenrong Xu1, Hui Qian1 
15 Nov 2017-American Journal of Translational Research (Am J Transl Res)-Vol. 9, Iss: 11, pp 4738-4746
TL;DR: The role of 14-3-3 proteins in the control of autophagy in cancer, neurodegenerative diseases and other pathological conditions is summarized.
Abstract: Autophagy is a cell digestion process that determines cell fate by promoting cell survival or inducing cell death in a cell context-dependent manner. Several classical signaling pathways, such as phosphoinositide-3-kinase and mammalian target of rapamycin, tightly regulate autophagy. 14-3-3 proteins regulate various signaling pathways by phosphorylation-dependent binding with partner proteins. 14-3-3 proteins also regulate autophagy by binding with autophagy-related proteins such as Beclin-1 and hVPS34. This review summarizes the role of 14-3-3 proteins in the control of autophagy in cancer, neurodegenerative diseases and other pathological conditions.
Citations
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Journal ArticleDOI
TL;DR: Current knowledge of the basic biochemistry and cellular function of LRRK2 is summarized to paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally.
Abstract: Since the discovery of leucine-rich repeat kinase 2 (LRRK2) as a protein that is likely central to the aetiology of Parkinson's disease, a considerable amount of work has gone into uncovering its basic cellular function. This effort has led to the implication of LRRK2 in a bewildering range of cell biological processes and pathways, and probable roles in a number of seemingly unrelated medical conditions. In this review we summarise current knowledge of the basic biochemistry and cellular function of LRRK2. Topics covered include the identification of phosphorylation substrates of LRRK2 kinase activity, in particular Rab proteins, and advances in understanding the activation of LRRK2 kinase activity via dimerisation and association with membranes, especially via interaction with Rab29. We also discuss biochemical studies that shed light on the complex LRRK2 GTPase activity, evidence of roles for LRRK2 in a range of cell signalling pathways that are likely cell type specific, and studies linking LRRK2 to the cell biology of organelles. The latter includes the involvement of LRRK2 in autophagy, endocytosis, and processes at the trans-Golgi network, the endoplasmic reticulum and also key microtubule-based cellular structures. We further propose a mechanism linking LRRK2 dimerisation, GTPase function and membrane recruitment with LRRK2 kinase activation by Rab29. Together these data paint a picture of a research field that in many ways is moving forward with great momentum, but in other ways has not changed fundamentally. Many key advances have been made, but very often they seem to lead back to the same places.

97 citations


Cites background from "14-3-3 proteins: an important regul..."

  • ...In the majority of cases, 14-3-3 proteins bind specifically to motifs containing phosphoserine or phosphothreonine, and thus protein-protein interactions involving 14-3-3 proteins are typically phosphorylation dependent [74]....

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Journal ArticleDOI
TL;DR: This study is the first to systematically identify several LD-associated proteins of the lipophagy machinery, a finding with important biological and therapeutic implications that may represent a novel strategy to treat atherosclerosis.
Abstract: Macrophage autophagy is a highly anti-atherogenic process that promotes the catabolism of cytosolic lipid droplets (LDs) to maintain cellular lipid homeostasis. Selective autophagy relies on tags s...

57 citations

Journal ArticleDOI
28 Sep 2019
TL;DR: The results indicate that 14-3-3t acts via a newly-discovered mechanism for the activation of autophagy by NSC-sEVs, further promoting functional behavior recovery following spinal cord injury.
Abstract: Neural stem cell-derived small extracellular vesicles (NSC-sEVs) play an important role in the repair of tissue damage. Our previous in vitro and in vivo studies found that preconditioning with NSC-sEVs promoted the recovery of functional behaviors following spinal cord injury by activating autophagy. However, the underlying mechanisms for such observations remain unclear. In this study, we further explored the mechanisms by which NSC-sEVs repair spinal cord injury via autophagy. We found that NSC-sEVs contain 14-3-3t protein, of which the overexpression or knockdown enhanced and decreased autophagy, respectively. In addition, 14-3-3t overexpression enhanced the anti-apoptotic and anti-inflammatory effects of NSC-sEVs, further promoting functional behavior recovery following spinal cord injury. The overexpression of 14-3-3t was used to further validate the in vivo results through a series of in vitro experiments. Conversely, knockdown of 14-3-3t attenuated the anti-apoptotic and anti-inflammatory effects of NSC-sEVs. Further studies also confirmed that NSC-sEVs increased Beclin-1 expression, with which 14-3-3t interacted and promoted its localization to autophagosome precursors. In this study, we found that NSC-sEVs deliver 14-3-3t, which interacts with Beclin-1 to activate autophagy. Our results indicate that 14-3-3t acts via a newly-discovered mechanism for the activation of autophagy by NSC-sEVs.

44 citations


Cites background from "14-3-3 proteins: an important regul..."

  • ...Multiple studies have shown that 14-3-3 proteins play important roles in the regulation of autophagy [20, 30, 31]....

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  • ...A significant reduction in Beclin-1 expression correlating with positive regulation of autophagy has been observed in U20S cell lines response expressing inducible or transient siRNA against 14-3-3t [30]....

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Journal ArticleDOI
TL;DR: The biological functions of 14‐3‐3 proteins in protein trafficking, cell‐cycle control, apoptosis, autophagy and other cell signal transduction pathways, as well as the associated mechanisms are summarized.
Abstract: 14-3-3 proteins are highly conserved in species ranging from yeast to mammals and regulate numerous signalling pathways via direct interactions with proteins carrying phosphorylated 14-3-3-binding motifs. Recent studies have shown that 14-3-3 proteins can also play a role in viral infections. This review summarizes the biological functions of 14-3-3 proteins in protein trafficking, cell-cycle control, apoptosis, autophagy and other cell signal transduction pathways, as well as the associated mechanisms. Recent findings regarding the role of 14-3-3 proteins in viral infection and innate immunity are also reviewed.

20 citations

Journal ArticleDOI
TL;DR: The activation of NF-kB is suggested as a possible pathway that links the deregulation of glutamate, calcium, apoptosis and the activation of the immune system in schizophrenia patients.
Abstract: Schizophrenia is a chronic disease characterized by the impairment of mental functions with a marked social dysfunction. A quantitative proteomic approach using iTRAQ labeling and SRM, applied to the characterization of mitochondria (MIT), crude nuclear fraction (NUC), and cytoplasm (CYT), can allow the observation of dynamic changes in cell compartments providing valuable insights concerning schizophrenia physiopathology. Mass spectrometry analyses of the orbitofrontal cortex from 12 schizophrenia patients and 8 healthy controls identified 655 protein groups in the MIT fraction, 1500 in NUC, and 1591 in CYT. We found 166 groups of proteins dysregulated among all enriched cellular fractions. Through the quantitative proteomic analysis, we detect as the main biological pathways those related to calcium and glutamate imbalance, cell signaling disruption of CREB activation, axon guidance, and proteins involved in the activation of NF-kB signaling along with the increase of complement protein C3. Based on our data analysis, we suggest the activation of NF-kB as a possible pathway that links the deregulation of glutamate, calcium, apoptosis, and the activation of the immune system in schizophrenia patients. All MS data are available in the ProteomeXchange Repository under the identifier PXD015356 and PXD014350.

18 citations

References
More filters
Journal ArticleDOI
11 Nov 2011-Cell
TL;DR: It is explored how recent mouse models in combination with advances in human genetics are providing key insights into how the impairment or activation of autophagy contributes to pathogenesis of diverse diseases, from neurodegenerative diseases such as Parkinson disease to inflammatory disorders such as Crohn disease.

4,529 citations


"14-3-3 proteins: an important regul..." refers background in this paper

  • ...The formation of double-membrane autophagosomes involves the following steps: induction, nucleation, elongation, and formation a complete isolation membrane [9]....

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Journal ArticleDOI
TL;DR: This review summarizes the current knowledge about the molecular machinery of autophagy and the role of the autophagic machinery in eukaryotic development and identifies a set of evolutionarily conserved genes that are essential forAutophagy.

3,721 citations


"14-3-3 proteins: an important regul..." refers background in this paper

  • ...Autophagy is classified into three subtypes: macroautophagy, microautophagy and chaperone-mediated autophagy [2]....

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Journal ArticleDOI
23 Sep 2005-Cell
TL;DR: Bcl-2 not only functions as an antiapoptotic protein, but also as an antiautophagy protein via its inhibitory interaction with Beclin 1, which may help maintain autophagy at levels that are compatible with cell survival, rather than cell death.

3,384 citations

Journal ArticleDOI
TL;DR: This work shows that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains, and provides proof-of-principle for the potential of inducing autophagy to treat Huntington disease.
Abstract: Huntington disease is one of nine inherited neurodegenerative disorders caused by a polyglutamine tract expansion. Expanded polyglutamine proteins accumulate abnormally in intracellular aggregates. Here we show that mammalian target of rapamycin (mTOR) is sequestered in polyglutamine aggregates in cell models, transgenic mice and human brains. Sequestration of mTOR impairs its kinase activity and induces autophagy, a key clearance pathway for mutant huntingtin fragments. This protects against polyglutamine toxicity, as the specific mTOR inhibitor rapamycin attenuates huntingtin accumulation and cell death in cell models of Huntington disease, and inhibition of autophagy has the converse effects. Furthermore, rapamycin protects against neurodegeneration in a fly model of Huntington disease, and the rapamycin analog CCI-779 improved performance on four different behavioral tasks and decreased aggregate formation in a mouse model of Huntington disease. Our data provide proof-of-principle for the potential of inducing autophagy to treat Huntington disease.

2,335 citations


"14-3-3 proteins: an important regul..." refers background in this paper

  • ...Ravikumar et al found that in fly and mouse models of Huntington’s disease, the inhibition of mTOR induces autophagy and eliminates the accumulation of polyglutamine [12]....

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Journal ArticleDOI
TL;DR: It is shown that heterozygous disruption of beclin 1 increases the frequency of spontaneous malignancies and accelerates the development of hepatitis B virus-induced premalignant lesions, providing genetic evidence that autophagy is a novel mechanism of cell-growth control and tumor suppression.
Abstract: Malignant cells often display defects in autophagy, an evolutionarily conserved pathway for degrading long-lived proteins and cytoplasmic organelles. However, as yet, there is no genetic evidence for a role of autophagy genes in tumor suppression. The beclin 1 autophagy gene is monoallelically deleted in 40-75% of cases of human sporadic breast, ovarian, and prostate cancer. Therefore, we used a targeted mutant mouse model to test the hypothesis that monoallelic deletion of beclin 1 promotes tumorigenesis. Here we show that heterozygous disruption of beclin 1 increases the frequency of spontaneous malignancies and accelerates the development of hepatitis B virus-induced premalignant lesions. Molecular analyses of tumors in beclin 1 heterozygous mice show that the remaining wild-type allele is neither mutated nor silenced. Furthermore, beclin 1 heterozygous disruption results in increased cellular proliferation and reduced autophagy in vivo. These findings demonstrate that beclin 1 is a haplo-insufficient tumor-suppressor gene and provide genetic evidence that autophagy is a novel mechanism of cell-growth control and tumor suppression. Thus, mutation of beclin 1 or other autophagy genes may contribute to the pathogenesis of human cancers.

2,168 citations


"14-3-3 proteins: an important regul..." refers background in this paper

  • ...4740 Am J Transl Res 2017;9(11):4738-4746 siRNA had the opposite effect [17]....

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